Primary vaginal signet ring cell carcinoma

Primary vaginal cancer is rare, accounting for only 2% of all gynecological malignant tumors. Primary vaginal cell carcinoma is mainly squamous cell carcinoma, accounting for about 90%, and adenocarcinoma only accounts for 8–10%. Primary signet ring cell carcinoma of vagina is rare and has not been reported in the literature. This paper reports a case of signet ring cell carcinoma in vagina.


CASE PRESENTATION
A 65-year-old female was admitted to the Second Affiliated Hospital of Zhejiang Chinese Medical University in April 2019, and she reported a vaginal bleeding after sexual intercourse in December 2018. Pelvic ultrasound demonstrated a pelvic hematoma, and pharmaceutical conservative treatment was administrated. However, she had intermittent vaginal bleeding in the following three months. 1 Considering that the patient previously underwent total hysterectomy for uterine prolapse, the uterine pathologic specimen was reviewed. The patient had neither cervical and endometrial dysplasia or carcinoma in situ (CIS) nor a history of exposure to diethylstilbestrol (DES), and she was negative for human papilloma virus (HPV). Physical examination revealed a palpable mass (6.0 × 6.0 cm) in the pelvic cavity, which was hard in texture and poor in mobility, without significant tenderness. A small amount of dark-red secretions were visible within the vagina, and the anterior vaginal wall was hard and presented with irregular nodules. Vaginal neoplastic lesion was considered, and tumor index test and pelvic enhanced MRI were performed. Laboratory examination revealed elevation of CA125 (63.4 U ml −1 ) and cytokeratin 19 fragment (3.17 U ml −1 ), and other normal tumor indices. On pelvic MRI, a mass with a predominant cyst component (around 5.9 × 4.5 × 8.9 cm in size), which enveloped the left lower ureter and closely adhered to the posterior bladder wall and the rectum, was found within the vagina. The mass was hypointense signal on T 1 weighted imaging (T 1 WI) (Figure 1a), heterogeneously hyperintense signal on T 2 weighted imaging fat suppression (T 2 WI-FS) (Figure 1b), and slightly hyperintense signal on diffusion-weighted imaging (DWI) (Figure 1c) with increased apparent diffusion coefficient (ADC) (Figure 1d). On enhanced MRI, the arterial phase showed mild enhancement of the margin and the mild grid-like enhancement of the interior of the mass with no enhancement in the cystic cavity ( Figure 1e); while the delayed phase showed further enhancement of the margin and the interior of the mass (Figure 1f ). A vaginal malignancy was suggested, and whether it was a metastasis needed to be validated. To confirm the pathology of the vaginal tumor, biopsy of the vaginal mass was suggested and approved by the patient. Pathologic findings showed that the mass was nodular segmented by fibrous tissues and rich in mucin within the stroma. The cells were in medium-size, and the majority of them showed clear cytoplasm rich in mucin and partial acidophilic cytoplasm. In addition, the nuclei were hyperchromatic and had a signet ring appearance after squeezing to one side with visible mitosis (Figure 2a). Immunohistochemistry showed CDX-2 (+) (Figure 2b), Villin (+) (Figure 2c), CK7 (+), GATA-3 (+), MUC-1 (weakly +), P53 (+), KI67 10%+ (CA125-, ER-, PR-). Combining the pathology and immunohistochemistry, vaginal signet ring cell carcinoma was diagnosed, while gastrointestinal tumor metastasis could not be excluded. Since primary vaginal tumor is rare, systemic examination is required to exclude metastasis. Vaginal signet ring cell carcinoma usually originates from gastrointestinal signet ring cell carcinoma and sometimes from breast and bladder signet ring cell carcinomas. Therefore, the patient was scheduled for gastroscopy, breast ultrasound, and abdominalenhanced CT. No significant abnormalities were found on both the gastroscopy and breast ultrasound. The uterus and bilateral adnexa were absent on abdominal CT. Besides, an irregular mass skewed to the left and sized around 5.9 × 4.5 × 8.9 cm was found within the vagina, presenting with heterogeneously slightly low density and spotty calcification of the margin. The left lower ureter was enveloped by the mass, and part of the mass was closely adhered to the posterior bladder wall and the rectum (Figure 3a). On enhanced CT scan, mild-to-moderate enhancement of the margin and mild grid-like enhancement in the interior of the mass were demonstrated (Figure 3b-c). There was no significant abnormality in the gastrointestinal tract or other abdominal organs. Vaginal malignancy was reported, and metastasis could not be excluded. Considering all the aforementioned evidence collectively, primary signet ring cell carcinoma was highly suspected. Positron emission tomography-computed tomography (PET-CT) was given to confirm whether the tumor was primary or metastatic, and a local malignant tumor within the vagina with no any other neoplastic lesion in other body sites was reported ( Figure 4). Combining the pathology, immunohistochemistry, and imaging results, primary vaginal signet ring cell carcinoma was diagnosed. The patient then underwent laparoscopic exploration under general anesthesia, showing absence of tumor in the abdominal organs (e.g. liver, gallbladder, pancreas, diaphragm, stomach, and intestine) or the upper abdominal peritoneum. Besides, adhesions were found between intestinal wall/peritoneum and vaginal stump/bladder wall. After the adhesions were separated, an extraperitoneal mass, which was approximately 9.0 × 5.0 × 5.5 cm in size with a hard texture, was found as protruding from the vaginal stump to the left posterior bladder. The left ureter was enveloped by the mass, and the posterior margin of the mass was tightly adhered to some rectum. Neither the uterus nor bilateral adnexa were observed. The surgery scope required to be expanded, but the patient family refused.

DISCUSSION
Primary vaginal cancer is rare. Most of these tumors are squamous cell carcinomas, while others are adenocarcinoma,  The pathogenesis of signet ring cell carcinoma of vagina is unclear. In 89% of cases, vaginal cancer may be a high-risk HPV-related disease. 1 There are also some literatures that hysterectomy is related to the occurrence of vaginal cancer. In the study of 91 patients with vaginal cancer conducted by Hiniker et al., 46% of patients have a history of hysterectomy, 7 and in the study of Mariana Lima et al., 80% of patients with vaginal adenocarcinoma have a history of hysterectomy. 8 At the same time, Clement's case report shows that adenocarcinoma and focal signet ring cells were found in vagina 15 months after hysterectomy. 4 The patient in our article underwent hysterectomy for uterine prolapse 3 years ago. At that time, the pathological result was benign, the patient had no history of exposure to DES and HPV was negative. Therefore, it is speculated that the occurrence  of signet ring cell carcinoma of vagina in this case may be related to hysterectomy.
The overall vaginal tumor reported here was slightly hypointense signal on T 1 WI, heterogeneously hyperintense signal on T 2 WI, and slightly hypointense signal on DWI with significant ADC value elevation. Additionally, the tumor presented with enhancement of the margin and grid-like enhancement in the interior of the mass. A previous study demonstrated that the hyperintense signal area on T 2 WI might indicate a mucin-producing tumor. 9 Consistently, the MRI findings suggested that the tumor was rich in mucin. Signet ring cell carcinoma is a type of mucinous adenocarcinoma rich in mucin. Tumor imaging features, such as MRI manifestations, fail to make a direct diagnosis of signet ring cell carcinoma but provide some indications. Moreover, CT images are capable of showing spotty calcification within a lesion, which is also a manifestation of signet ring cell carcinoma. In the study of Yang et al, 10 the calcification in signet ring cell carcinoma was considered as the deposition of calcium salts in the intra-or extracellular mucus lakes, which presented as punctate, miliary, or nodular calcific foci on CT images. Presently, the cause of calcification remains elusive, and it is speculated as correlated to the mucoricin within and alkaline environment of the mucus lakes. In terms of the MRI manifestations, signet ring cell carcinoma usually is slightly hypointense signal on T 1 WI and heterogeneously hyperintense signal on T 2 WI due to the large amount of mucous component. In addition, it is iso-to-hyperintense signal on DWI given the increase in the interstitial space of the tissue. Both enhanced CT and MRI images showed enhancement of the margin and grid-like enhancement in the interior of the tumor, which is also reflective of the mucous component. The grid-like enhancement in the interior of the tumor is considered a result of the presence of some interstitial and vascular components. 11 The differential diagnosis of signet ring cell carcinoma of vagina includes metastatic carcinoma, squamous cell carcinoma, clear cell carcinoma, melanoma, and sarcoma, among which metastatic carcinoma needs to be differentiated first. Signet ring cell carcinoma usually originates from gastrointestinal, manifesting diffuse thickening of the gastrointestinal wall with visible spotty or nodular calcification.
Additionally, it presents with layered delayed enhancement after enhanced scan. In the case reported here, spotty calcification was found within the lesion on CT scan and delayed enhancement was indicated after enhanced scan, similar to gastrointestinal signet ring cell carcinoma. [10][11][12] However, the present case showed a mass with a predominant cystic component due to the copious mucin, which is different with the gastrointestinal signet ring cell carcinoma. In case of suspicion for vaginal signet ring cell carcinoma, it is important to first identify whether there is a primary tumor. If no primary tumor is found, primary vaginal signet ring cell carcinoma will be considered; otherwise, imaging and pathology are further required to confirm the diagnosis. Because primary vaginal cancer is rare and complicated to treat, it should follow the principle of individualization, and the treatment plan should learn from the treatment methods of cervical cancer. 1 It is reported 13 that chemotherapy combined with radiotherapy and surgery can prolong the survival time of cervical signet ring cell carcinoma, especially systemic chemotherapy can control distant metastasis and improve the curative effect.

CONCLUSION
The morphology and immunohistochemistry of primary signet ring cell carcinoma of vagina are similar to those of gastrointestinal signet ring cell carcinoma, and it is difficult to diagnose it only by pathology and immunohistochemistry. The final diagnosis must be combined with imaging, pathology, and immunohistochemistry.

LEARNING POINTS
• Signet ring cell carcinoma is highly malignant, mainly occurring in gastrointestinal tract and rarely in vagina. • MRI can well reflect the mucous components of tumors and has certain diagnostic value for mucinous tumors. • The diagnosis of primary signet ring cell carcinoma of vagina remains a challenge. The final diagnosis must be combined with imaging, pathology, and immunohistochemistry.